Project Summary (30 lines of text) One of the underappreciated aspects of neuronal biology is that, as postmitotically-differentiated neurons become mature, they undergo dynamic changes to ensure that the mature nervous system is capable of long- term survival and function. Understanding these mechanisms that are critical for the long-term homeostasis of the adult brain is important as their dysfunction could increase the vulnerability of neurons to age-related neurodegeneration. We have identified miR-29 as a microRNA that is strikingly induced with neuronal maturation. miR-29 is not detectable during embryonic development, but its levels are induced more than 300 fold by 2 months and even greater by 6 months in the adult brain. In contrast to the high miR-29 levels that are maintained in the normal adult brains, miR-29 levels are markedly reduced in Alzheimer?s Disease patients. miR-29 is recognized to target many of the genes in the AD pathways including BACE1, ADAM10, PICALM, and NAV3. To evaluate the functional importance of miR-29, we recently generated mice in which miR-29 can be conditionally deleted. Mice deficient for miR-29, either in the whole body or in the brain, are born normal but then progressively decline, exhibiting neurological defects and early lethality. These results show that miR-29 has an essential function in the mature brain. Our hypothesis is that miR-29, while not needed for embryonic development, is physiologically important for maintaining long-term homeostasis in the adult brain. Reduction in miR-29 levels could therefore increase the vulnerability of mature neurons to become dysfunctional in the context of Alzheimer?s Disease. The overall focus of our proposal is to understand the endogenous mechanisms that maintain the very high levels of miR-29 in the normal brain, to critically examine the function on miR-29 is the adult brain, and to evaluate the therapeutic potential of miR-29 for Alzheimer?s Disease. Specifically, in Aim 1, we will test the hypothesis is that an increase in miR-29 transcription in mature neurons is a result of chromatin derepression. Importantly, we will also examine whether the substantial increase in miR-29 is a consequence of increased processing and stability in mature neurons. In Aim 2, we will focus on defining the molecular, cellular and behavioral consequences of deleting miR-29 in the adult brain. To evaluate the therapeutic potential of miR- 29 for Alzheimer?s Disease, we have also generated mice in which miR-29 can be conditionally overexpressed. Thus in Aim 3, we will examine whether overexpression of miR-29 is beneficial in the mutant APP knock-in mouse model of Alzheimer?s Disease. Overall, we are excited to be working on a molecule, miR-29, that has a unique and essential function in the mature brain. Our studies will help define its mechanisms of action as well as evaluate its therapeutic potential in the context of Alzheimer?s Disease.